Epoxy compound and method for manufacturing the same

ABSTRACT

The present invention provides a novel intermediate for manufacturing a 2,3-dihydroimidazo[2,1-b]oxazole compound with a high yield and a high purity, and a manufacturing method of the intermediate. The present invention provides an epoxy compound represented by the general formula (2): wherein, R1 represents a hydrogen or a lower alkyl group; and R2 represents a piperidyl group represented by the general formula (A1): (wherein, R3 represents a phenoxy group having a halogen-substituted lower alkoxy group substituted on a phenyl group, and the like) and the like; and n represents an integer of 1 to 6, a manufacturing method of the epoxy compound, and a manufacturing method of an oxazole compound using the epoxy method.

This application is a division of application Ser. No. 12/599,214, filedNov. 6, 2009, which is a Section 371 of International Application No.PCT/JP2008/058798, filed May 7, 2008, which claims priority of JapaneseApplication No. 2007-123097, filed May 8, 2007, the contents of all ofwhich are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to an epoxy compound and a method formanufacturing the same.

BACKGROUND ART

A 2,3-dihydroimidazo[2,1-b]oxazole compound or salts thereof are usefulcompounds as an antitubercular agent (WO2004/033463, WO2004/035547 andWO2005/042542), the oxazole compound or salts thereof are represented bythe general formula (1):

-   wherein R¹ represents hydrogen or a lower alkyl group;    -   R² represents a piperidyl group represented by the general        formula (A1):

-   (wherein R³ represents:-   (A1a) a phenoxy group having a halogen-substituted lower alkoxy    group(s) as a substituent(s) on a phenyl group,-   (A1b) a phenoxy-substituted lower alkyl group having a    halogen-substituted lower alkyl group(s) as a substituent(s) on a    phenyl group,-   (A1c) a phenyl-substituted lower alkoxy lower alkyl group having a    halogen(s) as a substituent(s) on a phenyl group,-   (A1d) a phenyl-substituted lower alkyl group having a    halogen-substituted lower alkoxy group(s) as a substituent(s) on a    phenyl group,-   (A1e) an amino group having a phenyl group having a    halogen-substituted lower alkoxy group(s) as a substituent(s) on a    phenyl group, and a lower alkyl group, or-   (A1f) a phenyl-substituted lower alkoxy group having a    halogen-substituted lower alkoxy group(s) as a substituent(s) on a    phenyl group), or a piperazyl group represented by the general    formula (A2):

-   (wherein R⁴ represents:-   (A2a) a phenyl-substituted lower alkenyl group having a    halogen-substituted lower alkoxy group(s) as a substituent(s) on a    phenyl group, or-   (A2b) a halogen-substituted phenyl group); and    n represents an integer of 1 to 6. These Patent Documents disclose,    as a manufacturing method of the 2,3-dihydroimidazo[2,1-b]oxazole    compound, for example, a method shown by the following Reaction    Formula A:

-   wherein R¹, R² and n are the same as in the above; and-   X¹ represents a halogen atom or a nitro group.

The above-mentioned oxazole compound is an important compound asantitubercular agent, and the development of alternative methods formanufacturing industrially and profitably the compound is much desired.

It is an object of the present invention to provide a novel intermediatefor manufacturing a 2,3-dihydroimidazo[2,1-b]oxazole compoundrepresented by the general formula (1) in a high yield and a highpurity, and a manufacturing method of the intermediate.

DISCLOSURE OF THE INVENTION

As a result of intensive studies on a manufacturing method of a2,3-dihydroimidazo[2,1-b]oxazole compound represented by the abovegeneral formula (1), the present inventors have found that using anepoxy compound represented by the below general formula (2) as astarting raw material enables to manufacture a2,3-dihydroimidazo[2,1-b]oxazole compound represented by the generalformula (1), which is an active principle of an anti-tubercular agent ina high yield and with a high purity. This finding has led to thecompletion of the present invention.

The present invention provides an epoxy compound or salts thereof, shownin Item 1 and Item 2 below.

Item 1:

To provide an epoxy compound or salts thereof represented by the generalformula (2):

-   wherein R¹ represents a hydrogen or a lower alkyl group;    -   R² represents a piperidyl group represented by the general        formula (A1):

-   (wherein R³ represents:-   (A1a) a phenoxy group having a halogen-substituted lower alkoxy    group(s) as a substituent(s) on a phenyl group,-   (A1b) a phenoxy-substituted lower alkyl group having a    halogen-substituted lower alkyl group(s) as a substituent(s) on a    phenyl group,-   (A1c) a phenyl-substituted lower alkoxy lower alkyl group having a    halogen(s) as a substituent(s) on a phenyl group,-   (A1d) a phenyl-substituted lower alkyl group having a    halogen-substituted lower alkoxy group(s) as a substituent(s) on a    phenyl group,-   (A1e) an amino group having a phenyl group having a    halogen-substituted lower alkoxy group(s) as a substituent(s) on a    phenyl group, and a lower alkyl group, or-   (A1f) a phenyl-substituted lower alkoxy group having a    halogen-substituted lower alkoxy group(s) as a substituent(s) on a    phenyl group), or a piperazyl group represented by the general    formula (A2):

-   (wherein R⁴ represents:-   (A2a) a phenyl-substituted lower alkenyl group having a    halogen-substituted lower alkoxy group(s) as a substituent(s) on a    phenyl group, or-   (A2b) a halogen-substituted phenyl group; and-   n represents an integer of 1 to 6.    Item 2:

To provide an epoxy compound or salts thereof selected from the groupconsisting of:

-   1)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine;-   2)    (R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine;-   3)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethylphenoxymethyl)piperidine;-   4)    (R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethylphenoxymethyl)piperidine;-   5)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperazine;-   6)    (R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperazine;-   7)    (R)-4-(4-chlorobenzyloxymethyl)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]piperidine;-   8)    (R)-4-(4-chlorobenzyloxymethyl)-1-[4-(2,3-epoxypropoxy)phenyl]piperidine;-   9)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxybenzyl)piperidine;-   10)    (R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethoxybenzyl)piperidine;-   11)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[N-methyl-N-(4-trifluoromethoxyphenyl)]aminopiperidine;-   12)    (R)-4-[N-methyl-N-(4-trifluoromethoxyphenyl)]amino-1-[4-(2,3-epoxypropoxy)phenyl]piperidine;-   13)    (R)-1-(4-chlorophenyl)-4-[4-(2,3-epoxy-2-methylpropoxy)phenyl]piperazine;-   14) (R)-1-(4-chlorophenyl)-4-[4-(2,3-epoxypropoxy)phenyl]piperazine;-   15)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxybenzyloxy)piperidine;    and-   16)    (R)-1-(4-(oxiranylmethoxy)phenyl)-4-(4-(trifluoromethoxy)benzyloxy)piperidine.

The present invention further provides a manufacturing method of anepoxy compound or salts thereof, shown in Item 3 below.

Item 3:

To provide a method for manufacturing an epoxy compound or salts thereofrepresented by the general formula (2):

-   wherein R¹, R² and n are the same as the above, by reacting a    compound or salts thereof represented by the general formula (3):

-   wherein R¹ and n are the same as the above; and-   X² represents a halogen or a group(s) causing a substitution    reaction similar to that of a halogen with a compound or salts    thereof represented by the general formula (4):

-   wherein R² is the same as the above.

The present invention further provides a manufacturing method of anoxazole compound or salts thereof shown in Item 4 below.

Item 4:

To provide a method for manufacturing an oxazole compound or saltsthereof represented by the general formula (1):

wherein R¹, R² and n are the same as the above, by reacting a compoundor salts thereof represented by the general formula (5):

wherein X¹ represents a halogen atom, with an epoxy compound or saltsthereof represented by the general formula (2):

wherein R¹, R² and n are the same as the above.

An epoxy compound or salts thereof of the general formula (2) accordingto the present invention is a novel compound which is not described inany documents.

An epoxy compound or salts thereof of the general formula (2) accordingto the present invention are useful as an intermediate for manufacturingan oxazole compound or salts thereof represented by the general formula(1), which is important as a synthesized intermediate for medicinals andagrichemicals, especially as an anti-tubercular agent.

An epoxy compound represented by the above general formula (2) ispreferably a compound or salts thereof selected from the groupconsisting of:

-   1)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-4-trifluoromethoxyphenoxy)piperidine;-   2)    (R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine;-   3)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethylphenoxymethyl)piperidine;-   4)    (R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethylphenoxymethyl)piperidine;-   5)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperazine;-   6)    (R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperazine;-   7)    (R)-4-(4-chlorobenzyloxymethyl)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]piperidine;-   8)    (R)-4-(4-chlorobenzyloxymethyl)-1-[4-(2,3-epoxypropoxy)phenyl]piperidine;-   9)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxybenzyl)piperidine;-   10)    (R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethoxybenzyl)piperidine;-   11)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[N-methyl-N-(4-trifluoromethoxyphenyl)]aminopiperidine;-   12)    (R)-4-[N-methyl-N-(4-trifluoromethoxyphenyl)]amino-1-[4-(2,3-epoxypropoxy)phenyl]piperidine;-   13)    (R)-1-(4-chlorophenyl)-4-[4-(2,3-epoxy-2-methylpropoxy)phenyl]piperazine;-   14) (R)-1-(4-chlorophenyl)-4-[4-(2,3-epoxypropoxy)phenyl]piperazine;-   15)    (R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxybenzyloxy)piperidine;    and-   16)    (R)-1-(4-(oxiranylmethoxy)phenyl)-4-(4-trifluoromethoxy)benzyloxy)piperidine.

Each group described in the present specification is specifically asfollows.

The halogen atoms include a fluorine atom, chlorine atom, bromine atomand iodine atom.

The lower alkoxy groups include, for example, linear or branched alkoxygroups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). Morespecifically, they include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy,1-ethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy,1,2,2-trimethylpropoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, isohexyloxyand 3-methylpentyloxy groups.

The halogen-substituted lower alkoxy groups include the lower alkoxygroups as mentioned above having 1 to 7, preferably 1 to 3, halogenatoms as a substituent(s). More specifically, they includefluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy,dichlorofluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy,2-chloroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy,heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy,4,4,4-trifluorobutoxy, 4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy,4-bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentyloxy,5-chloropentyloxy, 6,6,6-trifluorohexyloxy and 6-chlorohexyloxy groups.

The phenoxy groups having a halogen-substituted lower alkoxy group on aphenyl group as a substituent(s) include, for example, phenoxy groupshaving 1 to 3 (preferably 1) the halogen-substituted lower alkoxy groupsas mentioned above on a phenyl group as a substituent(s).

The lower alkyl groups include linear or branched alkyl groups having 1to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically,they include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl,n-hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl,isohexyl and 3-methylpentyl groups.

The halogen-substituted lower alkyl groups include the lower alkylgroups as mentioned above having 1 to 7, preferably 1 to 3, halogenatoms as a substituent(s). More specifically, they include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl,2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl,2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl,4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl,5,5,5-trifluoropentyl, 5-chloropentyl, 6,6,6-trifluorohexyl and6-chlorohexyl groups.

The phenoxy-substituted lower alkyl groups are exemplified by the loweralkyl groups as mentioned above having one phenoxy group as asubstituent. More specifically, they include phenoxymethyl,2-phenoxyethyl, 1-phenoxyethyl, 2-phenoxyethyl, 2-phenoxy-1-methylethyl,2-phenoxy-1-ethylethyl, 3-phenoxypropyl and 4-phenoxybutyl groups.

The phenoxy-substituted lower alkyl groups having a halogen-substitutedlower alkyl group(s) as a substituent(s) on a phenyl group include, forexample, the phenoxy-substituted lower alkyl groups as mentioned abovehaving 1 to 3 (preferably 1) halogen-substituted lower alkyl group(s) asmentioned above as a substituent(s) on a phenyl group.

The lower alkoxy lower alkyl groups are exemplified by the lower alkylgroups as mentioned above having one lower alkoxy group as mentionedabove as a substituent. More specifically, they include methoxymethyl,2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2-isobutoxyethyl,2,2-dimethoxyethyl, 2-methoxy-1-methylethyl, 2-methoxy-1-ethylethyl,3-methoxypropyl, 3-ethoxypropyl, 3-isobutoxypropyl, 3-n-butoxypropyl,4-n-propoxybutyl, 1-methyl-3-isobutoxypropyl,1,1-dimethyl-2-n-pentyloxyethyl, 5-n-hexyloxypentyl, 6-methoxyhexyl,1-ethoxyisopropyl and 2-methyl-3-methoxypropyl groups.

The phenyl-substituted lower alkoxy lower alkyl groups are exemplifiedby the lower alkoxy lower alkyl groups as mentioned above having onephenyl group as a substituent on a lower alkoxy group. Morespecifically, they include benzyloxymethyl, (2-phenylethoxy)methyl,(1-phenylethoxy)methyl, 3-(3-phenylpropoxy)propyl,4-(4-phenylbutoxy)butyl, 5-(5-phenylpentyloxy)pentyl,6-(6-phenylhexyloxy)hexyl, 1,1-dimethyl-(2-phenylethoxy)ethyl,2-methyl-3-(3-phenylpropoxy)propyl, 2-benzyloxyethyl, 1-benzyloxyethyl,3-benzyloxypropyl, 4-benzyloxybutyl, 5-benzyloxypentyl and6-benzyloxyhexyl groups.

The phenyl-substituted lower alkoxy lower alkyl groups having ahalogen(s) as a substituent(s) on a phenyl group include, for example,the phenyl-substituted lower alkoxy lower alkyl groups as mentionedabove having 1 to 7, more preferably 1 to 3, the halogen atom(s) as asubstituent(s) on a phenyl group.

The phenyl-substituted lower alkyl groups are exemplified by the loweralkyl groups as mentioned above having one phenyl group as asubstituent. More specifically, they include benzyl, 1-phenylethyl,2-phenylethyl, 1-methyl-1-phenylethyl, 1,1-dimethyl-2-phenylethyl,1,1-dimethyl-3-phenylpropyl, 3-phenylpropyl and 4-phenylbutyl groups.

The phenyl-substituted lower alkyl groups having a halogen-substitutedlower alkoxy group(s) as a substituent(s) on a phenyl group include, forexample, the phenyl-substituted lower alkyl groups as mentioned abovehaving 1 to 3 (preferably 1) halogen-substituted lower alkoxy groups asmentioned above as a substituent(s) on a phenyl group.

The phenyl groups having a halogen-substituted lower alkoxy group(s) asa substituent(s) on a phenyl group include, for example, phenyl groupshaving 1 to 3 (preferably 1) halogen-substituted lower alkoxy group(s)as a substituent(s) on a phenyl group.

The amino groups having a phenyl group having a halogen-substitutedlower alkoxy group(s) as a substituent(s) on a phenyl group and a loweralkyl group as a substituent include, for example, amino groups having,on an amino group, one phenyl group as mentioned above having ahalogen-substituted lower alkoxy group(s) as a substituent(s) on aphenyl group and one lower alkyl group.

The phenyl-substituted lower alkoxy groups are exemplified by the loweralkyl groups as mentioned above having one phenyl group as asubstituent. More specifically, they include benzyloxy, 1-phenylethoxy,2-phenylethoxy, 1-methyl-1-phenylethoxy, 1,1-dimethyl-2-phenylethoxy,1,1-dimethyl-3-phenylpropoxy, 3-phenylpropoxy and 4-phenylbutoxy groups.

The phenyl-substituted lower alkoxy groups having a halogen-substitutedlower alkoxy group(s) as a substituent(s) on a phenyl group include, forexample, the phenyl-substituted lower alkoxy groups having 1 to 3(preferably 1) halogen-substituted lower alkoxy group(s) as mentionedabove as a substituent(s) on a phenyl group.

The lower alkenyl groups include linear or branched alkenyl groupshaving 1 to 3 double bond(s) and having 2 to 6 carbon atoms, and includeboth the trans form and cis form. More specifically, they include vinyl,1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl,2-pentenyl and 1-pentenyl groups.

The phenyl-substituted lower alkenyl groups are exemplified by the loweralkenyl groups as mentioned above having one phenyl group as asubstituent. More specifically, they include 2-phenylvinyl,3-phenyl-1-propenyl, 3-phenyl-2-propenyl, 3-phenyl-1-methyl-1-propenyl,3-phenyl-2-methyl-1-propenyl, 3-phenyl-2-methyl-2-propenyl,4-phenyl-2-butenyl, 4-phenyl-1-butenyl, 4-phenyl-3-butenyl,5-phenyl-2-pentenyl and 5-phenyl-1-pentenyl groups.

The phenyl-substituted lower alkenyl groups having a halogen-substitutedlower alkoxy group(s) as a substituent(s) on a phenyl group include, forexample, the phenyl-substituted lower alkenyl groups as mentioned abovehaving 1 to 3 (preferably 1) halogen-substituted lower alkoxy group(s)as mentioned above as a substituent(s) on a phenyl group.

The halogen-substituted phenyl groups include, for example, the phenylgroup(s) as mentioned above having 1 to 7, preferably 1 to 3, halogenatom(s) as a substituent(s).

The manufacturing method of an epoxy compound of the general formula (2)according to the present invention will be described hereinafter.

[wherein, R¹, X² and n are the same as the above.]

The groups causing the substitution reaction similar to that of ahalogen atom represented by X² are exemplified by loweralkanesulfonyloxy groups, arylsulfonyloxy groups and aralkylsulfonyloxygroups.

The lower alkanesulfonyloxy groups are specifically exemplified bylinear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms,such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy,isopropanesulfonyloxy, n-butanesulfonyloxy, tert-butanesulfonyloxy,n-pentanesulfonyloxy and n-hexanesulfonyloxy groups.

The arylsulfonyloxy groups include, for example, phenylsulfonyloxy andnaphthylsulfonyloxy groups which may have 1 to 3 groups selected fromthe group consisting of linear or branched alkyl groups having 1 to 6carbon atoms, linear or branched alkoxy groups having 1 to 6 carbonatoms, nitro groups and halogen atoms as a substituent(s) on a phenylring. The phenylsulfonyloxy groups which may have the substituent(s) arespecifically exemplified by phenylsulfonyloxy,4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,2-nitrophenylsulfonyloxy and 3-chlorophenylsulfonyloxy groups. Thenaphthylsulfonyloxy groups are specifically exemplified byα-naphthylsulfonyloxy and β-naphthylsulfonyloxy groups.

The aralkylsulfonyloxy groups include, for example, linear or branchedalkanesulfonyloxy groups having a phenyl group(s) as a substituent(s)and having 1 to 6 carbon atoms or linear or branched alkanesulfonyloxygroups having a naphthyl group(s) as a substituent(s) and having 1 to 6carbon atoms which may have 1 to 3 groups selected from the groupconsisting of linear or branched alkyl groups having 1 to 6 carbonatoms, linear or branched alkoxy groups having 1 to 6 carbon atoms,nitro groups and halogen atoms as a substituent(s) on a phenyl ring. Thealkanesulfonyloxy groups having a phenyl group substituted arespecifically exemplified by benzylsulfonyloxy, 2-phenylethylsulfonyloxy,4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy,2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy,4-methoxybenzylsulfonyloxy and 3-chlorobenzylsulfonyloxy groups. Thealkanesulfonyloxy groups having a naphthyl group substituted arespecifically exemplified by α-naphthylmethylsulfonyloxy andβ-naphthylmethylsulfonyloxy groups.

A compound represented by the general formula (2) is manufactured byreacting a compound represented by the general formula (3) with acompound represented by the general formula (4).

The reaction of a compound represented by the general formula (3) with acompound represented by the general formula (4) is performed without asolvent or in an inert solvent and under the presence of a basiccompound or the absence thereof.

The inert solvents include, for example, water; ether solvents such asdioxane, tetrahydrofuran, dimethyl ether, diethyl ether, diethyleneglycol dimethyl ether and ethylene glycol dimethyl ether; aromatichydrocarbon solvents such as benzene, toluene and xylene; lower alcoholsolvents such as methanol, ethanol and isopropanol; ketone solvents suchas acetone and methyl ethyl ketone; and polar solvents such asN,N-dimethylformamide (DMF), dimethylacetamide, dimethylsulfoxide(DMSO), hexamethylphosphoric acid triamide and acetonitrile.

As the basic compounds, a wide variety of known ones can be used, whichinclude, for example, alkali metal hydroxides such as sodium hydroxide,potassium hydroxide, cesium hydroxide and lithium hydroxide; alkalimetal carbonates such as sodium carbonate, potassium carbonate, cesiumcarbonate and lithium carbonate; alkali metal hydrogencarbonates such aslithium hydrogencarbonate, sodium hydrogencarbonate and potassiumhydrogencarbonate; alkali metals such as sodium and potassium; inorganicbases such as sodium amide, sodium hydride and potassium hydride; alkalimetal lower alkoxides such as sodium methoxide, sodium ethoxide,potassium methoxide and potassium ethoxide; and organic bases such astriethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazadicyclo[5.4.0]undecene-7(DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO).

These basic compounds are used singly or as a mixture of two or more.

The using amount of a basic compound is usually 0.5 to 10 times mole,preferably 0.5 to 6 times mole to a compound of the general formula (3).

The above reaction may be performed, as required, by adding an alkalimetal iodide such as potassium iodide or sodium iodide, as a reactionaccelerator.

The ratio of the used amount of a compound of the general formula (3) toa compound of the general formula (4) in the above Reaction Formula-1 isusually 1 mole of the former to at least 0.5 mole, preferably about 0.5to 5 mole of the latter.

The above reaction is performed usually under the temperature conditionof room temperature to 200° C., preferably room temperature to 150° C.,and is generally completed in about 1 to 30 hours.

The above reaction may be performed under the presence of aphase-transfer catalyst. The phase-transfer catalysts to be usableinclude quaternary ammonium salts (quaternary ammonium salts substitutedby a group(s) selected from the group consisting of linear or branchedalkyl groups having 1 to 18 carbon atoms, phenyl-substituted lower alkylgroups and phenyl groups, such as tetrabutylammonium chloride,tetrabutylammonium bromide, tetrabutylammonium fluoride,tetrabutylammonium iodide, tetrabutylammonium hydroxide,tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride,tributylbenzylammonium chloride, tetrapentylammonium chloride,tetrapentylammonium bromide, tetrahexylammonium chloride,benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride,octadecyltrimethylammonium chloride, benzyldimethyloctadecanylammoniumchloride, methyltridecanylammonium chloride, benzyltripropylammoniumchloride, benzyltriethylammonium chloride, phenyltriethylammoniumchloride, tetraethylammonium chloride and tetramethylammonium chloride);linear or branched pyridinium salts having 1 to 18 carbon atoms, such as1-dodecanylpyridinium chloride; and phosphonium salts (phosphonium saltssubstituted by a linear or branched alkyl group(s) having 1 to 18 carbonatoms and/or phenyl-substituted lower alkyl groups, such astetrabuthylphosphonium chloride). In this case, the reaction ispreferably performed in water alone, or in a mixed solution with anorganic solvent immiscible with water (benzene, toluene, xylene,methylene chloride, 1,2-dichloroethane, etc.).

The ratio of the used amount of a compound represented by the generalformula (4) to a phase-transfer catalyst is usually one mole of theformer to 0.01 to 0.5 mole, preferably 0.2 to 0.3 mole of the latter.

When the above reaction is performed under the presence of aphase-transfer catalyst, the ratio of the used amount of a compoundrepresented by the general formula (3) to a compound represented by thegeneral formula (4) is one mole of the former to 0.7 to 1.5 mole,preferably 0.8 to 1.0 mole of the latter.

A compound represented by the general formula (4) used as a starting rawmaterial in the above reaction preferably has a form of lithium salt.The lithium salt of a compound represented by the general formula (4)has advantages of being stable and being easily handled. Further, thelithium salt of a compound represented by the general formula (4) iseasily synthesized in a suitable solvent from a compound represented bythe general formula (4) and lithium hydroxide. Therefore, the lithiumsalt to be used of a compound represented by the general formula (4)needs not be an isolated one, and may be one obtained by dissolving acompound represented by the general formula (4) and lithium hydroxide inwater.

Compounds represented by the general formulas (3) and (4) used asstarting raw materials in the reaction according to the presentinvention are well known.

The manufacturing method of oxazole compounds according to the presentinvention will be described hereinafter.

[wherein, R¹, R² and n are the same as the above. X¹ represents ahalogen atom.]

According to Reaction Formula-2, a compound represented by the generalformula (1) is manufactured by reacting a 4-nitroimidazole compoundrepresented by the general formula (5) with an epoxy compoundrepresented by the general formula (2) under the presence of a basiccompound or the absence thereof to obtain a compound represented by thegeneral formula (6), and subjecting the obtained compound represented bythe general formula (6) to a ring closure reaction.

The ratio of the used amount of a compound of the general formula (5) toa compound of the general formula (2) is usually one mole of the formerto 0.5 to 5 mole, preferably 0.5 to 3 mole of the former.

As the basic compounds, a wide variety of known ones can be used, whichinclude, for example, inorganic bases such as metal hydrides, alkalimetal lower alkoxides, hydroxides, carbonates and hydrogencarbonates,and organic bases such as acetates.

The metal hydrides are specifically exemplified by sodium hydride andpotassium hydride.

The alkali metal lower alkoxides are specifically exemplified by sodiummethoxide, sodium ethoxide and potassium tert-butoxide.

The hydroxides are specifically exemplified by sodium hydroxide andpotassium hydroxide. The carbonates are specifically exemplified bysodium carbonate and potassium carbonate.

The hydrogencarbonates are specifically exemplified by sodiumhydrogencarbonate and potassium hydrogencarbonate.

The inorganic bases also include sodium amides in addition to the above.

The acetates are specifically exemplified by sodium acetate andpotassium acetate. The organic salts in addition to the above arespecifically exemplified by triethylamine, trimethylamine,diisopropylethylamine, pyridine, dimethylaniline, 1-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]undecene-7 (DBU) and1,4-diazabicyclo[2.2.2]octane (DABCO).

Such a basic compound is used usually in 0.1 to 2 mole, preferably 0.1to 1 mole, more preferably 0.1 to 0.5 mole to one mole of a compound ofthe general formula (5).

The reaction of a compound of the general formula (5) and a compound ofthe general formula (2) is performed usually in a suitable solvent.

As the solvents, a wide variety of known ones can be used, as long asthey do not inhibit the reaction, and include, for example, aproticpolar solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO)and acetonitrile; ketone solvents such as acetone and methyl ethylketone; hydrocarbon solvents such as benzene, toluene, xylene, tetralinand liquid paraffin; alcoholic solvents such as methanol, ethanol,isopropanol, n-butanol and tert-butanol; ether solvents such astetrahydrofuran (THF), dioxane, dipropyl ether, diethyl ether anddiglyme; ester solvents such as ethyl acetate and methyl acetate; andmixtures thereof. These solvents may contain water.

The reaction of a compound of the general formula (5) with a compound ofthe general formula (2) is performed, for example, by dissolving thecompound of the general formula (5) in a reaction solvent, adding abasic compound to the solution at an ice-cooling temperature to roomtemperature (30° C.) under stirring, stirring the mixture at roomtemperature to 80° C. for 30 minute to 1 hour, thereafter adding thecompound of the general formula (2), and continuing stirring the mixturenormally at room temperature to 100° C., preferably at 50 to 80° C. for30 minute to 60 hours, preferably for 1 to 50 hours.

The compound (5) used as a raw material is a well-known compound. Thecompound of the present invention represented by the general formula (1)is manufactured by subjecting a compound represented by the generalformula (6) to a ring closure reaction. The ring closure reaction isperformed by dissolving the compound obtained in the above representedby the general formula (6) in a reaction solvent, and adding a basiccompound thereto and stirring the mixture.

As the reaction solvents and the basic compounds, which the reactionsolvents and the basic compounds used in the reaction of a compound ofthe general formula (5) and a compound of the general formula (2) asdescribed above can be used.

The using amount of a basic compound is usually 1 to an excessive mole,preferably 1 to 5 mole, more preferably 1 to 2 mole to one mole of acompound of the general formula (6).

The reaction temperature of the ring closure reaction is usually at 0 to150° C., preferably at room temperature to 120° C., more preferably at50 to 100° C. The reaction time is usually 30 minute to 48 hours,preferably 1 to 24 hours, more preferably 1 to 12 hours.

In the present invention, the reaction mixture of a compound of thegeneral formula (5) and a compound of the general formula (2) can beprovided to the following ring closure reaction without isolating acompound of the general formula (6) produced by the reaction thereof. Atarget compound represented by the general formula (1) can also bemanufactured, for example, by reacting a compound of the general formula(5) with a compound of the general formula (2) at room temperature to80° C., then adding a basic compound to the reaction mixture, andfurther stirring the mixture at 50 to 100° C., or by reacting a compoundof the general formula (5) with a compound of the general formula (2) atroom temperature to 80° C., then condensing the reaction mixture,dissolving the residue in a high-boiling point solvent, adding a basiccompound to the obtained solution, and further stirring the solution at50 to 100° C.

A target compound represented by the general formula (1) can also bemanufactured by using 0.9 to 2 mole of a basic compound to one mole of acompound of the general formula (5) in the reaction of the compound ofthe general formula (5) and a compound of the general formula (2), andstirring the reaction mixture at 50 to 100° C. to react the compound ofthe general formula (5) and the compound of the general formula (2) at asingle process.

Compounds represented by the general formula (5) used as a starting rawmaterial in the reaction according to the present invention are wellknown.

Raw material compounds used in the each reaction formula described abovemay be suitable salts, and target compounds obtained by the eachreaction may form suitable salts. These suitable salts are thosepharmacologically acceptable salts, and include salts of inorganicbases, those of organic bases, those of inorganic acids and those oforganic acids.

The salts of inorganic bases include, for example, metal salts such asalkali metal salts (e.g., lithium salts, sodium salts and potassiumsalts) and alkaline earth metal salts (e.g. calcium salts and magnesiumsalts), ammonium salts, alkali metal carbonates (e.g. lithium carbonate,potassium carbonate, sodium carbonate and cesium carbonate), alkalimetal hydrogencarbonates (e.g. lithium hydrogencarbonate, sodiumhydrogencarbonate and potassium hydrogencarbonate), and alkali metalhydroxides (e.g. lithium hydroxide, sodium hydroxide, potassiumhydroxide and cesium hydroxide).

The salts of organic bases include, for example, tri(lower)alkylamine(e.g. trimethylamine, triethylamine and N-ethyldiisopropylamine),pyridine, quinoline, piperidine, imidazole, picoline,dimethylaminopyridine, dimethylaniline, N-(lower)alkylmorpholine (e.g.N-methylmorpholine), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and1,4-diazabicyclo[2.2.2]octane (DABCO).

The salts of inorganic acids include, for example, hydrochlorides,hydrobromides, hydroiodides, sulfates, nitrates and phosphates.

The salts of organic acids include, for example, those such as formates,acetates, propionates, oxalates, malonates, succinates, fumarates,maleates, lactates, malates, citrates, tartrates, citrates, carbonates,picrates, methanesulfonates, ethanesulfonates, p-toluenesulfonates andglutamates.

Compounds having forms in which solvates (e.g. hydrates and ethanolates)are added to raw materials and target compounds indicated in the eachreaction formula are included in the each general formula. Preferablesolvates include hydrates.

The each target compound obtained in the above each reaction formula canbe isolated and purified from a reaction mixture, for example, byseparating a crude reaction product through isolation operations such asfiltration, condensation and extraction after a reaction mixture iscooled, and subjecting the separated reaction product to commonpurification operations such as column chromatography andrecrystallization.

The compounds represented by the general formula (1) according to thepresent invention naturally include isomers such as geometrical isomers,stereoisomers and optical isomers.

In the case where a 2,3-dihydroimidazo[2,1-b]oxazole compoundrepresented by the general formula (1) or salts thereof, which is anactive principle of tuberculostatic, is manufactured by reacting anepoxy compound or salts thereof of the present invention represented bythe general formula (2) with a compound represented by the generalformula (5), remarkably slight amounts of by-products are produced alongwith the reaction. Accordingly, using the epoxy compound of the presentinvention represented by the general formula (2) or salts thereofenables to manufacture a 2,3-dihydroimidazo[2,1-b]oxazole compoundrepresented by the general formula (1) with a higher yield and a higherpurity.

The epoxy compound of the present invention represented by the generalformula (2) or salts thereof is a compound which is easily crystallized.Therefore, the epoxy compound of the present invention represented bythe general formula (2) or salts thereof can be obtained with a highpurity by a simple crystallization operation after the reaction of acompound represented by the general formula (3) or salts thereof with acompound represented by the general formula (4).

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be more clarified by way ofReference Examples and Examples.

Reference Example 1 1-ethoxycarbonyl-4-methyloxypiperidine

1-ethoxycarbonyl-4-hydroxypiperidine (30.3 g) and triethylamine (23 g)were dissolved in ethyl acetate (182 mL) and the obtained mixture wascooled to 3° C. Methanesulfonyl chloride (22.05 g) was added theretounder stirring while taking caution such that the temperature did notexceed 20° C., and the mixture was continuously stirred under icecooling for 1 hour. The obtained reaction mixture was washed with water(90 mL×3). The organic layer was isolated and concentrated to obtain atarget compound as a light yellow oily substance. The yield amount was43.09 g (98%).

¹H-NMR (CDCl₃, 300 MHz); 1.27 (3H, t, J=7.1 Hz), 1.8-1.9 (2H, m),1.9-2.05 (2H, m), 3.05 (3H, s), 3.3-3.45 (2H, m), 3.69-3.8 (2H, m), 4.14(2H, q, J=7.1 Hz), 4.86-4.94 (1H, m).

Reference Example 21-ethoxycarbonyl-4-(4-trifluoromethoxyphenoxy)piperidine

1-ethoxycarbonyl-4-mesyloxypiperidine (13.6 g), trifluoromethoxyphenol(4.0 g), tetrabutylammonium chloride (1.2 g) and potassium carbonate(7.72 g) were suspended in water (20 mL) and the suspension was refluxedfor 3 hours. The reaction solution was cooled to room temperature, andthen the reaction product was extracted with toluene (24 mL). Theextract was washed with water (20 mL×2), and then the solvent wasconcentrated under reduced pressure to obtain a target compound as alight yellow oily substance. The yield amount was 12.03 g (%). Theobtained target compound was used, for the subsequent reaction withoutbeing purified.

¹H-NMR (CDCl₃, 300 Hz); 1.27 (3H, t, J=7.1 Hz), 1.7-1.8 (2H, m),1.89-2.0 (2H, m), 3.3-3.46 (2H, m), 3.68-3.77 (2H, m), 4.14 (2H, q,J=7.1 Hz), 4.43-4.47 (1H, m), 6.89 (2H, d, J=9.1 Hz), 7.13 (2H, d, J=9.1Hz).

Reference Example 3 4-(4-trifluoromethoxyphenoxy)piperidine

Potassium hydroxide (10.7 g) was heated to 100° C., and dissolved inisobutanol (15 mL). An isobutanol (25 mL) solution of1-ethoxycarbonyl-4-(4-trifluoromethoxyphenoxy)piperidine (12.03 g) wasdropwise added thereto while noticing generation of carbon dioxide gas.After the dropwise addition, the mixture was heated and stirred at 100°C. for 2 hours; then the solvent was concentrated; and toluene (40 mL)was added to the obtained residue. The toluene solution was washed withwater (40 mL×2), and then the solvent was concentrated under reducedpressure to obtain a target compound as a light orange solid substance.The yield amount was 5.73 g (98% based on trifluoromethoxyphenol).

¹H-NMR (CDCl₃, 300 Hz); 1.59-1.71 (2H, m), 1.95-2.05 (2H, m), 2.68-2.77(2H, m), 3.11-3.18 (2H, m), 4.29-4.37 (1H, m), 6.90 (2H, d, J=9.1 Hz),7.13 (2H, d, J=9.1 Hz).

Reference Example 44-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol.paratoluenesulfonicacid salt

4-(4-trifluoromethoxyphenoxy)piperidine (4.0 g), 1,4-cyclohexanedione(2.575 g) and triethylamine (2.16 mL) were dissolved in ethanol (60 mL),and the obtained mixture was heated at 50 to 60° C., and reacted for 6hours under air bubbling. After the reaction, the solvent was distilledoff under reduced pressure; ethyl acetate (20 mL) andparatoluenesulfonic acid monohydrate (4.37 g) were added to the obtainedresidue; the obtained mixture was cooled, and stirred for 1 hour. Theprecipitated crystal was filtered, and washed with a small amount ofethyl acetate, and then dried at room temperature to obtain a targetcompound as a light yellow power crystal. The yield amount was 4.465 g(55.5%).

Melting point: 211 to 214° C. (decomposing)

Purity (HPLC): 82.52%

HPLC conditions column: COSMOSIL5C8-MS (4.6φ×250 mm); detectionwavelength: 275 nm; elution condition 1: methanol/0.1M ammonium acetateaqueous solution=50/50 (40° C.); elution condition 2: methanol/0.1Mammonium acetate aqueous solution=800/200; purity=100−(the sum total ofimpurities detected on elution conditions 1 and 2)

¹H-NMR (DMSO-d₆ measurement temperature 70° C.); 2.05 (2H, m), 2.23 (2H,m), 2.28 (3H, s), 3.48 (2H, m). 3.59 (2H, m), 4.71 (1H, m), 6.87 (2H,m), 7.09 (2H, m), 7.13 (2H, m), 7.28 (2H, m), 7.38 (2H, m), 7.50 (2H, m)IR (KBr, cm⁻¹); 2714, 1506, 1288, 1217, 1033, 813

This compound could be further purified by recrystallizing from a mixedsolution of ethyl acetate of ten-times volume and water of two-timesvolume, and drying at 60° C.

Form: colorless scaly crystal

Purity (HPLC): 99.8% (HPLC conditions were the same as the above)

Melting point of its pure product: 218.1 to 219.3° C. (decomposing)

Reference Example 54-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol

Potassium carbonate (19.3 kg) was dissolved in water (245 L), and whilethe obtained solution was stirred at 20 to 30° C.,4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol.paratoluenesulfonicacid salt (49 kg) was added to the solution. The mixture wascontinuously stirred, for 1 hour; and then the crystal was filtered, andwashed with water (245 L) (until the washing liquid exhibitedneutrality). The obtained crystal was dried at about 60° C. for 42hours. The yield amount was 31.87 kg (yield: 96.74%).

Brownish powder, Melting point: 114 to 115° C.

¹H-NMR; (300 MHz; DMSO-d₆) 1.71-1.78 (2H, m), 2.0-2.05 (2H, m),2.81-2.89 (2H, m), 3.2-3.3 (2H, m), 4.50-4.51 (1H, m), 6.64 (2H, dd, J=3Hz, J=9 Hz), 6.80 (2H, dd, J=3 Hz, J=9 Hz), 7.06 (2H, dd, J=3 Hz, J=9Hz), 7.27 (2H, d, J=9 Hz), 8.82 (1H, s).

Reference Example 6 Lithium4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenolate

4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol.paratoluenesulfonicacid salt (105 g) and potassium carbonate (41.5 g) were added in water(525 mL), and the obtained mixture was stirred at room temperature for 2hours. The precipitated crystal was filtered, and dissolved inisopropylalcohol (525 mL); and a solution in which lithium hydroxidemonohydrate (8.0 g) was dissolved in water (45 mL) was added to thecrystal solution. The obtained mixture was stirred at room temperaturefor 2 hours; the reaction solution was concentrated to 3/5 under reducedpressure; the residual liquid was added with toluene, and concentratedunder reduced pressure till the liquid amount became about 1/4. Theresidue was added with toluene (200 mL); and the crystal was filtered,dried at 40 to 50° C. over night to obtain a target lithium salt as aslightly brown crystal. The yield amount was 66.6 g (93%).

¹H-NMR (300 MHz, DMSO-d₆) δ; 1.6-1.8 (2H, m), 1.9-2.1 (2H, m), 2.6-2.8(2H, m), 3.0-3.2 (2H, m), 4.3-4.5 (1H, m), 6.1-6.4 (2H, br), 6.57 (2H,d, J=8 Hz), 7.07 (2H, d, 9 Hz), 7.27 (2H, d, J=9 Hz).

Reference Example 7 Preparation of4-[4-(Trifluoromethoxy)phenoxy]pyridine-N-oxide

4-Nitropyridine-N-oxide (84.00 g), 4-Trifluoromethoxyphenol (107.8 g),K₂CO₃ (165.7 g) and DMF (420 mL) were placed in a vessel and stirred at80-90° C. for 4.5 hr. The reaction mixture was then cooled to roomtemperature and water (2500 mL) and ethyl acetate (2500 mL) were added.The organic material was taken up in ethyl acetate and then the aqueouslayer was extracted with ethyl acetate (1000 mL). The all organicextracts were washed three times with water (1000 mL×3). And then theorganic extracts were condensed under reduced pressure to give the crudeproducts (150.7 g). The crude products (150.7 g) and n-hexane (1500 mL)were placed in a vessel and stirred at 60° C. for 0.5 hr and then themixture was allowed to cool to under 10° C. for 1 hr. The mixture wasthen filtered and the crystalline powder washed with n-hexane (168 mL)and dried at 50° C. for 17 hr to afford 139.4 g (85.73% yield) of abrown crystal target compound.

Mp 108.5-109.5° C.

¹H-NMR (300 MHz, CDCl₃) δ=6.86-6.89 (m, 2H), 7.11-7.14 (m, 2H),7.29-7.32 (m, 2H), 8.15-8.18 (m, 2H)

Reference Example 8 Preparation of4-[4-(Trifluoromethoxy)phenoxy]pyridine

4-Chloropyridine hydrochloride (17.3 g), 4-Trifluoromethoxyphenol (24.6g), K₂CO₃ (35.1 g) and DMF (173 mL) were placed in a vessel and stirredat 28-40° C. for 1.5 hr. and then stirred at 75-84° C. for 6 hr. andthen stirred at 139-146° C. for 34.5 hr. The reaction mixture was thencooled to room temperature and water (256 mL), a small amount of NaCland ethyl acetate (256 mL) were added. The organic material was taken upin ethyl acetate. The organic layer was washed with water (256 mL) and asmall amount of NaCl. And then the organic layer was extracted threetimes with 10 v/v % HCl (256 mL×3). The organic material was taken up in10 v/v % HCl. And then the aqueous layer was basified to pH 9 by NaOHand was extracted with ethyl acetate (256 mL). The organic material wastaken up in ethyl acetate. The organic layer was washed with water (256mL) and a small amount of NaCl. The organic layer was condensed underreduced pressure to give 15.3 g (52.0% yield) of a brown oily targetcompound.

¹H-NMR (300 MHz, CDCl₃) δ=6.84-6.87 (m, 2H), 7.11-7.15 (m, 2H),7.26-7.30 (m, 2H), 8.49-8.53 (m, 2H)

Reference Example 9 Preparation of4-[4-(Trifluoromethoxy)phenoxy]pyridine

After 4-[4-(Trifluoromethoxy)phenoxy]pyridine-N-oxide (130.0 g) wasdissolved in ethanol (500 mL) and (50% wet) 5 w/w % palladium on carbon(6.5 g) was added. The resulting mixture was stirred under 3 atms ofatmosphere of hydrogen at 27-49° C. for 6.5 hr. The reaction mixture wasfiltered to remove the catalyst followed by concentration in vacuo togive a quantitative yield (122.9 g) of pale yellow oily crude product.Purification by flash column chromatography (600 g of Silica Gel 60,spherical, ethyl acetate) afforded the pure target compound product as acolorless oil (86.74 g, 70.91% yield).

¹H-NMR (300 MHz, CDCl₃) δ=6.84-6.86 (m, 2H), 7.11-7.15 (m, 2H),7.27-7.30 (m, 2H), 8.47-8.51 (m, 2H)

Reference Example 10 Preparation of4-[4-(Trifluoromethoxy)phenoxy]pyridine

After 4-[4-(Trifluoromethoxy)phenoxy]pyridine-N-oxide (50 mg) wasdissolved in ethanol (1.8 mL) and 10 w/w % palladium on carbon (4 mg)was added. And then Ammonium formate (120 mg) was added. The resultingmixture was stirred at 20° C. for 6 hr. The reaction mixture wasfiltered to remove the catalyst followed by concentration in vacuo togive a residual substance. And the a residual substance was extractedwith dichloromethane. The extract was condensed under reduced pressureto give 46 mg (98% yield) of a colorless oily target compound.

¹H-NMR (300 MHz, CDCl₃) δ=6.84-6.88 (m, 2H), 7.11-7.15 (m, 2H),7.26-7.31 (m, 2H), 8.49-8.51 (m, 2H)

Reference Example 11 Preparation of4-[4-(Trifluoromethoxy)phenoxy]piperidine

After 4-[4-(Trifluoromethoxy)phenoxy]pyridine (2.00 g) was dissolved inacetic acid (20 mL) and platinum(IV) oxide (200 mg) was added. Theresulting mixture was stirred under 4 atms of atmosphere of hydrogen at23-30° C. for 12 hr. The reaction mixture was filtered to remove thecatalyst followed by concentration in vacuo to give 3.32 g of yellowoily crude product. The crude product was dissolved in toluene (100 mL)and was washed three times with 10 w/v % NaOHaq (50 mL×3) and then waswashed three times with water (50 mL×3). The organic layer was condensedunder reduced pressure to give 675 mg (33.0% yield) of a pale yellowcrystal target compound.

¹H-NMR (300 MHz, CDCl₃) δ=1.50-1.60 (bs, 1H), 1.60-1.68 (m, 2H),1.98-2.03 (m, 2H), 2.68-2.76 (m, 2H), 3.10-3.18 (m, 2H), 4.28-4.36 (m,1H), 6.83-6.92 (m, 2H), 7.09-7.15 (m, 2H)

Reference Example 12 Preparation of4-[4-(Trifluoromethoxy)phenoxy]piperidine

After 4-[4-(Trifluoromethoxy)phenoxy]pyridine (2.00 g) was dissolved inacetic acid (20 mL) and platinum(IV) oxide (200 mg) was added. Theresulting mixture was stirred under 50 atms of atmosphere of hydrogen at24-26° C. for 7 hr 40 min. The reaction mixture was filtered to removethe catalyst followed by concentration in vacuo to give 3.89 g ofcolorless oily crude product. The crude product was dissolved in toluene(100 mL) and was washed three times with 10 w/v % NaOHaq (50 mL×3) andthen was washed three times with water (50 mL×3). The organic layer wascondensed under reduced pressure to give 772 mg (37.7% yield) of a paleyellow crystal target compound.

¹H-NMR (300 MHz, CDCl₃) δ=1.50-1.60 (bs, 1H), 1.60-1.67 (m, 2H),1.97-2.03 (m, 2H), 2.68-2.76 (m, 2H), 3.10-3.17 (m, 2H), 4.28-4.37 (m,1H), 6.86-6.92 (m, 2H), 7.09-7.15 (m, 2H)

Reference Example 13 Preparation of1-(4-Benzyloxyphenyl)-4-[4-(Trifluoromethoxy)phenoxy]piperidine

4-[4-(Trifluoromethoxy)phenoxy]piperidine (26.1 g), benzyl 4-bromophenylether (26.3 g), palladium (II) acetate (22.4 mg), Tri-tert-butylphosphonium tetraphenyl borate (52.3 mg), sodium tert-butoxide (10.6 g)and toluene (130 mL) were placed in a vessel and heated to reflux for 4hr under Ar. The reaction mixture was then cooled to room temperatureand water (260 mL) and ethyl acetate (260 mL) were added. The organicmaterial was taken up in ethyl acetate. The organic layer was washed twotimes with water (260 mL×2). The organic layer was filtered to remove aharz and then the organic layer was condensed under reduced pressure togive 43.34 g (97.82% crude yield, 97.34% HPLC purity) of the pale yellowproduct. The crude product (43.3 g) and ethanol (433 mL) were placed ina vessel and heated until to dissolve and then the mixture was allowedto cool to 0° C. for 1 hr. The mixture was then filtered and thecrystalline powder washed with cooled ethanol (43 mL) and then dried at40° C. for 15 hr to afford 39.7 g (91.7% yield) of a pale yellow crystaltarget compound.

Total yield 89.7%

HPLC purity 100%

¹H-NMR (300 MHz, CDCl₃) δ=1.93-2.00 (m, 2H), 2.07-2.11 (m, 2H),2.94-3.02 (m, 2H), 3.33-3.40 (m, 2H), 4.37-4.41 (m, 1H), 5.02 (s, 2H),6.89-6.92 (m, 2H), 7.11-7.15 (m, 2H), 7.31-7.44 (m, 5H)

Reference Example 14 Preparation of1-(4-Benzyloxyphenyl)-4-[4-(Trifluoromethoxy)phenoxy]piperidine

4-[4-(Trifluoromethoxy)phenoxy]piperidine (2.61 g), benzyl 4-bromophenylether (2.63 g), palladium (II) acetate (0.67 mg), Tri-tert-butylphosphonium tetraphenyl borate (1.57 mg), sodium tert-butoxide (1.06 g)and toluene (13 mL) were placed in a vessel and heated to reflux for 6hr under Ar. The reaction mixture was then cooled to room temperatureand water (100 mL) and ethyl acetate (100 mL) were added. The organicmaterial was taken up in ethyl acetate. The organic layer was washedthree times with water (100 mL×3). The organic layer was filtered toremove harz and then the organic layer was condensed under reducedpressure to afford 4.36 g (98.4% yield) of a pale yellow crystal targetcompound.

¹H-NMR (300 MHz, CDCl₃) δ=1.93-1.99 (m, 2H), 2.07-2.11 (m, 2H),2.93-3.01 (m, 2H), 3.32-3.39 (m, 2H), 4.38-4.40 (m, 1H), 5.02 (s, 2H),6.89-6.91 (m, 2H), 7.11-7.15 (m, 2H), 7.30-7.41 (m, 5H)

Reference Example 15 Preparation of1-(4-Hydroxyphenyl)-4-[4-(Trifluoromethoxy)phenoxy]piperidine

After 1-(4-Benzyloxyphenyl)-4-[4-(Trifluoromethoxy)phenoxy]piperidine(20.0 g) and ethyl alcohol (200 mL) was mixed and then (50% wet) 5 w/w %palladium on carbon (1 g) was added. The resulting mixture was stirredunder 4 atms of atmosphere of hydrogen at 60-61° C. for 3 hr. Thereaction mixture was then cooled to room temperature and was filtered toremove the catalyst followed by concentration in vacuo to give 16.2 g(99.5% yield) of an ivory crystal target compound.

HPLC purity 99.67%

¹H-NMR (300 MHz, CDCl₃) δ=1.93-2.00 (m, 2H), 2.08-2.13 (m, 2H),2.93-3.01 (m, 2H), 3.30-3.38 (m, 2H), 4.38-4.43 (m, 1H), 5.1 (bs, 1H),6.72-6.75 (m, 2H), 6.87-6.92 (m, 4H), 7.12-7.15 (m, 2H)

Reference Example 16 Synthesis of tert-butyl4-(4-trifluoromethoxybenzyloxy)piperidin-1-carboxylate

10.00 kg of tert-butyl 4-hydroxypiperidin-1-carboxylate, 40 L ofdimethoxyethane and 9.55 kg of sodium tert-butoxide were mixed, andstirred at 2 to 17° C. for 30 min. The mixture was mixed with 13.31 kgof 4-bromomethyl-1-trifluoromethoxybenzene and 10 L of dimethoxyethaneat 12 to 14° C., and stirred at 21 to 23° C. for 3 hours. The reactionmixture was diluted with 100 L of water; extracted with 100 L of ethylacetate; and the organic layer was washed with 100 L of a 1% NaClaqueous solution twice. The organic layer was concentrated under reducedpressure to quantitatively obtain 19.21 kg of a yellow oily targetsubstance.

Yield: 103%

¹H-NMR (300 MHz, CDCl₃) δ=1.46 (s, 9H), 1.50-1.67 (m, 2H), 1.80-1.97 (m,2H), 3.07-3.23 (m, 2H), 3.50-3.60 (m, 1H), 3.70-3.90 (m, 2H), 4.54 (s,2H), 7.19 (d, 2H, 8.7 Hz), 7.37 (d, 2H, 8.7 Hz)

Reference Example 17 Synthesis of4-(4-trifluoromethoxybenzyloxy)piperidine

19.21 kg of tert-butyl4-(4-trifluoromethoxybenzyloxy)piperidin-1-carboxylate and 50 L ofethanol were mixed, and stirred at 60° C. The mixture was mixed with8.28 L of a concentrated hydrochloric acid, stirred at 60° C. for 2hours, and concentrated under reduced pressure. 80 L of toluene wasadded to the residue; the mixture was extracted with 150 L of water; andfurther the water layer was washed with 40 L of toluene. 15.5 L of a 25%NaOH aqueous solution was added to the water layer; the mixture wasextracted twice with 80 L and 40 L of toluene; the organic layers werecombined and the organic layer was twice washed with 80 L of water; theorganic layer was concentrated under reduced pressure; then, 20 L ofethanol was added to the residue; and the mixture was concentrated underreduced pressure to obtain 10.40 kg of a yellow oily target substance.

Yield: 76.04%

¹H-NMR (300 MHz, CDCl₃) δ=1.42-1.62 (m, 2H), 1.90-2.05 (m, 2H),2.57-2.73 (m, 2H), 3.04-3.20 (m, 2H), 3.42-3.58 (m, 1H), 4.55 (s, 2H),7.18 (d, 2H, 8.7 Hz), 7.38 (d, 2H, 8.7 Hz)

Reference Example 18 Synthesis of1-(4-hydroxyphenyl)-4-(4-trifluoromethoxybenzyloxy)piperidine4-methylbenzenesulfonic acid

30.0 g of 4-(4-trifluoromethoxybenzyloxy)piperidine, 18.3 g of1,4-cyclohexanedione, 11.04 g of triethylamine and 150 mL of ethanolwere mixed. After stirring at 55° C. for 7.5 hours under air-blowing(310 mL/min), the mixture was concentrated under reduced pressure. Theresidue was mixed with 60 mL of ethyl acetate; the mixture wasconcentrated under reduced pressure; 150 mL of ethyl acetate and 31.2 gof 4-methylbenzenesulfonic acid were added to the mixture; the mixturewas stirred at 10° C. or less for 3 hours; then, the crystal wasfiltered, and dried at 60° C. over night to obtain 42.5 g of an ivorycrystal target substance.

Yield: 72.3%

HPLC purity: 92.2%

¹H-NMR (300 MHz, DMSO-d₆) δ=1.70-2.40 (m, 4H), 2.29 (s, 3H), 3.30-4.10(m, 5H), 4.61 (s, 2H), 6.88 (d, 2H, 8.6 Hz), 7.11 (d, 2H, 8.4 Hz), 7.37(d, 2H, 7.9 Hz), 7.40-7.80 (m, 6H)

Example 1(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine

4-[4-(4-trifluoromethoxyphenoxy)piperidine-1-yl]phenol (21.20 kg) wasdissolved in acetone (164 L) under stirring, and cooled to 10° C. orless. Sodium t-butoxide (6.34 kg) was added thereto under stirring whiletaking caution such that the temperature of the mixed liquid did notexceed 25° C. The mixed liquid was cooled to 10° C. or less;(R)-2-methylglycidyl paranitrobenzenesulfonate (16.40 kg) was addedthereto; and then the obtained mixture was heated at 40° C., and stirredfor 4 hours. The reaction liquid was added with water (164 L), cooled to10° C. or less; and the obtained mixture was stirred for 1 hour. Theprecipitated crystal was filtered, and washed with water (82 L). Theobtained crystal was dried at about 50° C. for 20 hours to obtain atarget substance as a grayish yellow crystalline powder. The yield was23.61 kg (92.91%). This crystal was used in the subsequent reactionwithout being purified. A part of the crystal was recrystallized fromethanol.

Melting point: 85.8 to 86.5° C.

Purity: 89.76% HPLC), HPLC conditions column: InertsilC8 (4.6φ×150 mm),detection wavelength: 254 nm, mobile phase composition: 0.025M phosphatebuffer aqueous solution/tetrahydrofuran/acetonitrile=400/300/300,measurement temperature: 40° C.

Optical purity: 96.1% ee (HPLC), HPLC conditions column: CHIRALPACK AD-H(4.0φ×250 mm), mobile phase composition:n-hexane/ethanol/diethylamine=900:100:1

¹H-NMR (300 MHz, CDCl₃) δ: 1.48 (3H, s), 1.9-2.1 (4H, m), 2.72 (1H, d,J=5 Hz), 2.86 (1H, d, J=5 Hz), 2.9-3.1 (2H, m), 3.3-3.5 (2H, m), 3.91(1H, d, J=10 Hz), 3.98 (1H, d, J=10 JHz), 4.3-4.5 (1H, m), 6.8-7.0 (6H,m), 7.14 (2H, d, J=9 Hz).

Example 2(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine

Lithium 4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenolate (66.6g), (R)-2-methylglycidyl paranitrobenzenesulfonate (49.1 g) andtetrabutylammonium chloride (15.5 g) were added to a mixed liquid oftoluene (200 mL) and water (333 mL), and the mixture was stirred at 60°C. for 6 hours. The reaction liquid was cooled to room temperature; thenthe toluene layer was isolated, and washed with water; then the solventwas distilled off under reduced pressure. Isopropyl alcohol (140 mL) andwater (60 mL) were added to the residue, and the obtained mixture wasstirred at 60° C. for 30 min. The stirred mixture was cooled; then theprecipitated crystal was filtered, and washed with a small amount ofhydrated isopropyl alcohol, and dried at 50° C. over night to obtain atarget substance as an orange crystal. The yield amount was 63.5 g(78%).

The crystal was recrystallized from isopropyl alcohol to obtain acolorless acicular crystal of 84 to 85° C. in melting point.

Purity: 94.6% (HPLC), HPLC conditions column: InertsilC8 (4.6φ×150 mm),detection wavelength: 254 nm, mobile phase composition: 0.025M phosphatebuffer aqueous solution/tetrahydrofuran/acetonitrile=400/300/300,measurement temperature: 40° C.

Optical purity: 90% ee (HPLC), HPLC conditions column: CHIRALPACK AD-H(4.6φ×250 mm), mobile phase composition:n-hexane/ethanol/diethylamine=900:100:1

¹H-NMR (300 MHz, CDCl₃) δ: 1.48 (3H, s), 1.9-2.1 (4H, m), 2.72 (1H, d,J=5 Hz), 2.86 (1H, d, J=5 Hz), 2.9-3.1 (2H, m), 3.3-3.5 (2H, m), 3.91(1H, d, J=10 Hz), 3.98 (1H, d, J=10 JHz), 4.3-4.5 (1H, m), 6.8-7.0 (6H,m), 7.14 (2H, d, J=9 Hz).

Example 3(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine

4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol.paratoluenesulfonicacid salt (5.0 g) and lithium hydroxide monohydrate (0.9 g) were addedto a mixed liquid of toluene (5 mL) and water (20 mL), and the obtainedmixture was stirred at 40 to 50° C. for 1 hour. The reaction liquid wascooled to 30 to 40° C.; then a aqueous solution (5 mL) of(R)-2-methylglycidyl paranitrobenzenesulfonate (2.86 g) andtetrabutylammonium chloride (0.52 g), and toluene (5 mL) were added tothe reaction liquid; and the mixture was stirred at 80° C. for 2 hours.After the mixture was cooled, the toluene layer was isolated, and washedwith water; and the solvent was distilled off. Methanol (25 mL) wasadded to the residue; the mixture was heated and dissolved; then thesolution was stirred under ice cooling for about 30 to 60 min; water (10mL) was slowly added when a crystal precipitated, and the mixture wasstirred for 15 min. The precipitated crystal was filtered, and washedwith a small amount of hydrated methanol, and dried at 50° C. over nightto obtain a target substance as a yellow crystal. The yield amount was3.89 g (84%).

Its purity: 83% (HPLC), HPLC conditions column: InertsilC8 (4.6φ×150mm), detection wavelength: 254 nm, mobile phase composition: 0.025Mphosphate buffer aqueoussolution/tetrahydrofuran/acetonitrile=400/300/300, measurementtemperature: 40° C.

Optical purity: 85% ee (HPLC), HPLC conditions column: CHIRALPACK AD-H(4.6φ×250 mm), mobile phase composition:n-hexane/ethanol/diethylamine=900:100:1

¹H-NMR (300 MHz, CDCl₃) δ: 1.48 (3H, s), 1.9-2.1 (4H, m), 2.72 (1H, d,J=5 Hz), 2.86 (1H, d, J=5 Hz), 2.9-3.1 (2H, m), 3.3-3.5 (2H, m), 3.91(1H, d, J=10 Hz), 3.98 (1H, d, J=10 JHz), 4.3-4.5 (1H, m), 6.8-7.0 (6H,m), 7.14 (2H, d, J=9 Hz).

Example 4(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine

An acetone (100 ml) solution of4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol (12.93 g) wascooled at 5° C., and sodium t-butoxide (3.87 g) was added thereto. Themixture, which generated heat to about 10° C., was stirred for 30 min,including a cooling time to 5° C.; and then (R)-2-methylglycidylparanitrobenzene sulfonate (10 g) was at once added to the mixture at 5°C. The mixture was stirred at 35 to 40° C. The reaction was pursuited byHPLC, and since the reaction finally was not seen to progress, thereaction was finished at 6 hours. Water (100 mL) was added to thereaction vessel; and the reaction mixture was stirred at 10° C. or lessfor 30 min. The reaction mixture was filtered, and washed with water(100 mL) to obtain a target compound of 18.63 g as a wet crystal (crudeyield: 120.2%). The water content was 24.4% (Karl Fisher's method). Theyield was determined by the quantification by HPLC; the reduced yieldwas 83.50% and the HPLC purity was 86.33%.

HPLC reaction pursuiting conditions: TSK ODS-80Ts (4.6×150 mm), 20 mMNa₂SO₄ aq/CH₃CN/THF (3:3:3), UV 254 nm, 1 ml/min, rt.

Example 5(R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine

A target compound was manufactured as in Example 1, using4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol and(R)-glycidylnosylate as starting raw materials.

Melting point: 67.5 to 68.7° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.83-2.17 (4H, m), 2.67-2.75 (1H, m),2.83-3.02 (3H, m), 3.25-3.40 (3H, m), 3.93 (1H, dd, J=5.6 Hz, J=11.1Hz), 4.17 (1H, dd, J=3.3 Hz, J=11.1 Hz), 4.31-4.45 (1H, m), 6.79-6.93(6H, m), 7.14 (2H, d, J=8.8 Hz).

Compounds of Examples 6 to 18 described below were manufactured as inExamples 1 to 5, using suitable starting raw materials.

Example 6(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethylphenoxymethyl)piperidine

Melting point: 129.0 to 129.4° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.46 (3H, s), 1.51-1.70 (2H, m), 1.84-2.09(3H, m), 2.58-2.78 (3H, m), 2.85 (1H, d, J=4.9 Hz), 3.52 (2H, d, J=11.9Hz), 3.79-4.03 (4H, m), 6.77-7.04 (6H, m), 7.54 (2H, d, J=8.6 Hz).

Example 7(R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethylphenoxymethyl)piperidine

Melting point: 131 to 131° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.45-1.64 (2H, m), 1.83-2.02 (3H, m),2.62-2.75 (3H, m), 2.80-2.88 (1H, m), 3.26-3.43 (1H, m), 3.50-3.64 (2H,m), 3.81-3.93 (3H, m), 4.17 (1H, dd, J=3.3 Hz, J=11.0 Hz), 6.78-7.00(6H, m), 7.54 (2H, d, J=8.7 Hz).

Example 8(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperazine

Melting point: 106.2 to 106.7° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.47 (3H, s), 2.56-2.76 (5H, m), 2.85 (1H, d,J=4.8 Hz), 3.02-3.30 (6H, m), 3.83-4.01 (2H, m), 6.18-6.36 (1H, m), 6.52(1H, d, J=15.9 Hz), 6.79-6.94 (4H, m), 7.16 (2H, d, J=8.2 Hz), 7.33-7.46(2H, m).

Example 9(R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperazine

Melting point: 88.2 to 89.5° C.

¹H-NMR (250 MHz, CDCl₃) δ: 2.60-2.79 (5H, m), 2.81-2.93 (1H, m),3.05-3.36 (7H, m), 3.92 (1H, dd, J=5.6 Hz, J=11.1 Hz), 4.16 (1H, dd,J=3.3 Hz, J=11.1 Hz), 6.82 (1H, dt, J=6.7 Hz, 15.9 Hz), 6.55 (1H, d,J=15.9 Hz), 6.81-6.93 (4H, m), 7.16 (2H, d, J=8.1 Hz), 7.40 (2H, d,J=8.1 Hz).

Example 10(R)-4-(4-chlorobenzyloxymethyl)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]piperidine

¹H-NMR (250 MHz, CDCl₃) δ: 1.29-1.54 (5H, m), 1.63-1.98 (3H, m),2.51-2.69 (2H, m), 2.73 (1H, d, J=4.8 Hz), 2.86 (1H, d, J=4.8 Hz), 3.34(2H, d, J=6.3 Hz), 3.53 (2H, d, J=12.0 Hz), 3.93 (2H, dd, J=10.5 Hz,J=15.4 Hz), 4.47 (2H, s), 6.72-6.95 (4H, m), 7.18-7.37 (4H, m).

Example 11(R)-4-(4-chlorobenzyloxymethyl)-1-[4-(2,3-epoxypropoxy)phenyl]piperidine

Melting point: 49 to 50° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.29-1.50 (2H, m), 1.64-1.93 (3H, m), 2.62(2H, dt, J=2.4 Hz, 12.0 Hz), 2.69-2.75 (1H, m), 2.82-2.90 (1H, m),3.25-3.40 (3H, m), 3.43-3.59 (2H, m), 3.92 (1H, dd, J=5.5 Hz, J=11.0Hz), 4.15 (1H, dd, J=3.3 Hz, J=11.0 Hz), 4.48 (2H, s), 6.79-6.93 (4H,m), 7.21-7.63 (4H, m).

Example 12(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxybenzyl)piperidine

¹H-NMR (250 MHz, CDCl₃) δ: 1.31-1.84 (8H, m), 2.43-2.67 (4H, m), 2.72(1H, d, J=4.8 Hz), 2.85 (1H, d, J=4.8 Hz), 3.47 (2H, d, J=12.1 Hz), 3.91(2H, dd, J=10.5 Hz, J=15.9 Hz), 6.75-6.97 (4H, m), 7.07-7.24 (4H, m).

Example 13(R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethoxybenzyl)piperidine

Melting point: 62.5 to 63.9° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.31-1.49 (2H, m), 1.52-1.78 (3H, m),2.45-2.63 (4H, m), 2.67-2.76 (1H, m), 2.78-2.88 (1H, m), 3.26-3.38 (1H,m), 3.43-3.57 (2H, m), 3.92 (1H, d, J=5.5 Hz, 11.1 Hz), 4.15 (1H, d,J=3.3 Hz, 11.1 Hz), 6.76-6.90 (4H, m), 7.05-7.26 (4H, m).

Example 14(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[N-methyl-N-(4-trifluoromethoxyphenyl)]aminopiperidine

Melting point: 74.0 to 74.7° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.47 (3H, s), 1.69-2.11 (4H, m), 2.61-2.90(7H, m), 3.43-3.75 (3H, m), 3.92 (2H, dd, J=10.5 Hz, J=17.8 Hz),6.64-6.82 (2H, m), 6.84-6.99 (4H, m), 7.01-7.17 (2H, d, J=8.5 Hz).

Example 15(R)-4-[N-methyl-N-(4-trifluoromethoxyphenyl)]amino-1-[4-(2,3-epoxypropoxy)phenyl]piperidine

Melting point: 92 to 93° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.75-2.02 (4H, m), 2.64-2.93 (7H, m),3.26-3.40 (1H, m), 3.55-3.75 (3H, m), 3.93 (1H, dd, J=5.6 Hz, J=11.0Hz), 4.17 (1H, dd, J=3.3 Hz, J=11.0 Hz), 6.77 (2H, d, J=8.5 Hz),6.81-6.95 (4H, m), 7.09 (2H, d, J=8.5 Hz).

Example 16(R)-1-(4-chlorophenyl)-4-[4-(2,3-epoxy-2-methylpropoxy)phenyl]piperazine

Melting point: 169.9 to 170.6° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.48 (3H, s), 2.73 (1H, d, J=4.8 Hz), 2.86(1H, d, J=4.8 Hz), 3.07-3.41 (8H, m), 3.93 (2H, dd, J=10.5 Hz, J=18.9Hz), 6.83-6.99 (6H, m), 7.14-7.32 (2H, m).

Example 17(R)-1-(4-chlorophenyl)-4-[4-(2,3-epoxypropoxy)phenyl]piperazine

Melting point: 177.5 to 178.5° C.

¹H-NMR (250 MHz, CDCl₃) δ: 2.69-2.79 (1H, m), 2.83-2.92 (1H, m),3.17-3.38 (9H, m), 3.94 (1H, dd, J=5.6 Hz, J=11.0 Hz), 4.18 (1H, dd,J=3.2 Hz, J=11.0 Hz), 6.81-6.98 (6H, m), 7.23 (2H, d, J=9.0 Hz).

Example 18(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxybenzyloxy)piperidine

Melting point: 97.6 to 97.9° C.

¹H-NMR (250 MHz, CDCl₃) δ: 1.47 (3H, s), 1.71-1.93 (2H, m), 1.96-2.16(2H, m), 2.70 (1H, d, J=4.8 Hz), 2.76-2.93 (3H, m), 3.31-3.64 (3H, m),3.93 (2H, dd, J=10.5 Hz, J=16.5 Hz), 4.57 (2H, s), 6.75-6.96 (4H, m),7.18 (2H, d, J=8.6 Hz), 7.39 (2H, d, J=8.6 Hz).

Example 19(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine(8.04 g), 2-bromo-4-nitroimidazole (4.53 g) and sodium acetate (387 mg)were mixed, and stirred at 110° C. for 2 hours. Dimethylformamide (20ml) was added to the reaction liquid, and after the contents weredissolved, the reaction liquid was cooled by ice. Dimethylformamide (70ml) was further added and the reaction liquid was cooled to −5° C.Sodium t-butoxide (2.949 g) was little by little added to the reactionliquid such that the temperature did not exceed 0° C. After about 3hours, water (200 mL) and ethyl acetate (10 mL) were added to thereaction liquid, and stirred at 60° C. for 1 hour. The reaction liquidwas cooled to 30° C., and the precipitated crystal was filtered, andwashed with water (45 mL) and with methanol (20 mL). The crystal wassuspended in a mixed liquid of ethyl acetate (25 mL) and methanol (25mL), and again stirred at 60° C. for 1 hour. The suspension was cooledto 5° C., and the precipitated crystal was filtered, and then dried (at60° C. over night) to obtain a target compound. The yield amount was7.258 g (71.5%); and the purity was 99.49% (HPLC).

HPLC conditions column: ODS-0TS (4.6φ×150 mm), detection wavelength: 254nm, mobile phase composition: 0.02M sodiumsulfate/tetrahydrofuran/acetonitrile=400/300/300, measurementtemperature: 40° C.

Optical purity: 99.6% ee (HPLC), HPLC conditions column: CHIRALPACK AD-H(4.6φ×250 mm), detection wavelength: 254 nm, mobile phase composition:n-hexane/ethanol/diethylamine=300/700/1

¹H-NMR (300 MHz, CDCl₃); 1.77 (3H, s), 1.8-2.2 (4H, m), 2.9-3.1 (2H, m),3.2-3.4 (2H, m), 3.9-4.1 (2H, m), 4.02 (1H, d, J=10 Hz), 4.04 (1H, d,J=10 Hz), 4.18 (1H, d, J=10 Hz), 4.4-4.5 (1H, m), 4.50 (1H, d, J=10 Hz),6.78 (2H, d, J=9 Hz), 6.8-7.0 (4H, m), 7.14 (2H, d, J=9 Hz), 7.56 (1H,s).

Example 20(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine(2.0 g) and 2-bromo-4-nitroimidazole (1.0 g) were dissolved in t-butylacetate (2 mL); sodium acetate (77.5 mg) was added thereto; and themixture was stirred at 95 to 100° C. for 3 hours. N,N-dimethyl aceticacid amide (18 mL) and lithium hydroxide monohydrate (238 mg) were addedto the obtained solution, and the mixture was stirred at 80° C. for 4hours. The reaction liquid was cooled, then added with water (35 mL) andstirred; and the precipitated crystal was filtered. The obtained crystalwas recrystallized from a mixed liquid of methanol (20 mL) and ethylacetate (4 mL), and dried at 60° C. over night to obtain a targetsubstance as a light yellow crystal. The yield amount was 1.79 g (yield:71%).

Purity: 100% (HPLC), HPLC conditions column: ODS-0TS (4.6φ×150 mm),detection wavelength: 254 nm, mobile phase composition: 0.02M sodiumsulfate/tetrahydrofuran/acetonitrile=400/300/300, measurementtemperature: 40° C.

Optical purity: 93.7% ee (HPLC), HPLC conditions column: CHIRALPACK AD-H(4.6φ×250 mm), detection wavelength: 254 nm, mobile phase composition:n-hexane/ethanol/diethylamine=300/700/1

¹H-NMR (300 MHz, CDCl₃); 1.77 (3H, s), 1.8-2.2 (4H, m), 2.9-3.1 (2H, m),3.2-3.4 (2H, m), 3.9-4.1 (2H, m), 4.02 (1H, d, J=10 Hz), 4.04 (1H, d,J=10 Hz), 4.18 (1H, d, J=10 Hz), 4.4-4.5 (1H, m), 4.50 (1H, d, J=10 Hz),6.78 (2H, d, J=9 Hz), 6.8-7.0 (4H, m), 7.14 (2H, d, J=9 Hz), 7.56 (1H,s).

Example 21(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine(2.0 g, purity: 86%) and 2-bromo-4-nitroimidazole (1.0 g) were dissolvedin t-butyl acetate (2 mL); sodium acetate (0.2 g) was added thereto; andthe mixture was stirred at 95 to 100° C. for 3 hours. Methanol (5.5 mL)was added to the obtained solution; and then a methanol solution (2.1mL) of 28% of sodium methylate was dropwise added to the solution at −10to 0° C. The obtained mixture was stirred at 0° C. for 30 min; water (15mL) was dropwise added to the mixture; and then ethyl acetate (1.1 mL)was added. Thereafter, the obtained mixture was heated at 45 to 55° C.,stirred for 1 hour, and then the precipitated crystal was filtered. Theobtained crystal was recrystallized from a mixed liquid of methanol (13mL) and ethyl acetate (13 mL), and dried at 60° C. over night to obtaina target substance as a white crystal. The yield amount was 1.31 g(purity-reduced yield: 60%).

Purity: 99.7% (HPLC), HPLC conditions column: ODS-0TS (4.6φ×150 mm),detection wavelength: 254 nm, mobile phase composition: 0.02M sodiumsulfate/tetrahydrofuran/acetonitrile=400/300/300, measurementtemperature: 40° C.

Optical purity: 99.5% ee (HPLC), HPLC conditions column: CHIRALPACK AD-H(4.6φ×250 mm), detection wavelength: 254 nm, mobile phase composition:n-hexane/ethanol/diethylamine=300/700/1

¹H-NMR (300 MHz, CDCl₃); 1.77 (3H, s), 1.8-2.2 (4H, m), 2.9-3.1 (2H, m),3.2-3.4 (2H, m), 3.9-4.1 (2H, m), 4.02 (1H, d, J=10 Hz), 4.04 (1H, d,J=10 Hz), 4.18 (1H, d, J=10 Hz), 4.4-4.5 (1H, m), 4.50 (1H, d, J=10 Hz),6.78 (2H, d, J=9) Hz), 6.8-7.0 (4H, m), 7.14 (2H, d, J=9 Hz), 7.56 (1H,s).

Example 22(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine(23.66 g, purity: 86%) and 2-bromo-4-nitroimidiazole (10.90 g) weredissolved in t-butyl acetate (20 mL); sodium acetate (775 mg) was addedthereto; and the mixture was stirred at 95 to 100° C. for 3 hours.Methanol (60 mL) was added to the obtained solution; and then thesolution was dropwise added to a solution in which sodium hydroxide (5.0g) was dissolved in methanol (40 mL) at −10 to 0° C. The obtainedmixture was stirred at 0° C. for 1 hour and 30 min; then water (100 mL)was dropwise added to the mixture; and then ethyl acetate (11 mL) wasadded. Thereafter, the obtained mixture was heated at 45 to 55° C.,stirred for 1 hour, and then the precipitated crystal was filtered. Theobtained crystal was recrystallized from a mixed liquid of methanol (160mL) and ethyl acetate (160 mL), and dried at 60° C. over night to obtaina target substance as a light yellow crystal. The yield amount was 17.05g (purity-reduced yield: 67.5%).

Purity: 99.9% (HPLC), HPLC conditions column: ODS-0TS (4.6φ×150 mm),detection wavelength: 254 nm, mobile phase composition: 0.02M sodiumsulfate/tetrahydrofuran/acetonitrile=400/300/300, measurementtemperature: 40° C.

Optical purity: 98.9% ee (HPLC), HPLC conditions column: CHIRALPACK AD-H(4.6φ×250 mm), detection wavelength: 254 nm, mobile phase composition:n-hexane/ethanol/diethylamine=300/700/1

1H-NMR (300 MHz, CDCl3); 1.77 (3H, s), 1.8-2.2 (4H, m), 2.9-3.1 (2H, m),3.2-3.4 (2H, m), 3.9-4.1 (2H, m), 4.02 (1H, d, J=10 Hz), 4.04 (1H, d,J=10 Hz), 4.18 (1H, d, J=10 Hz), 4.4-4.5 (1H, m), 4.50 (1H, d, J=10 Hz),6.78 (2H, d, J=9 Hz), 6.8-7.0 (4H, m), 7.14 (2H, d, J=9 Hz), 7.56 (1H,s).

Example 23(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine(23.66 g, purity: 84.5%) and 2-bromo-4-nitroimidazole (10.9 g) weredissolved in t-butyl acetate (20 mL); sodium acetate (775 mg) was addedthereto; and the mixture was stirred at 95 to 100° C. for 3 hours.Methanol (100 mL) was added to the obtained solution; and then a 25%sodium hydroxide aqueous solution (20.00 g) was dropwise added to thesolution at −10 to 0° C. The mixture was stirred at 0° C. for 2 hours;then water (84 mL) was dropwise added to the mixture; and then ethylacetate (11 mL) was added. Thereafter, the mixture was heated at 45 to55° C., stirred for 1 hour, and then the precipitated crystal wasfiltered. The obtained crystal was recrystallized from a mixed liquid ofmethanol (160 mL) and ethyl acetate (160 mL), and dried at 60° C. overnight to obtain a target substance as a light yellow crystal. The yieldamount was 16.80 g (purity-reduced yield: 66.5%).

Purity: 99.8% (HPLC), HPLC conditions column: ODS-0TS (4.6φ×150 mm),detection wavelength: 254 nm, mobile phase composition: 0.02M sodiumsulfate/tetrahydrofuran/acetonitrile=400/300/300, measurementtemperature: 40° C.

Optical purity: 99.1% ee (HPLC), HPLC conditions column: CHIRALPACK AD-H(4.6φ×250 mm), detection wavelength: 254 nm, mobile phase composition:n-hexane/ethanol/diethylamine=300/700/1

1H-NMR (300 MHz, CDCl3); 1.77 (3H, s), 1.8-2.2 (4H, m), 2.9-3.1 (2H, m),3.2-3.4 (2H, m), 3.9-4.1 (2H, m), 4.02 (1H, d, J=10 Hz), 4.04 (1H, d,J=10 Hz), 4.18 (1H, d, J=10 Hz), 4.4-4.5 (1H, m), 4.50 (1H, d, J=10 Hz),6.78 (2H, d, J=9 Hz), 6.8-7.0 (4H, m), 7.14 (2H, d, J=9 Hz), 7.56 (1H,s).

Example 24(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

The(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole,obtained in Examples 19 to 23, had a sufficiently high purity, but thepurity could be further raised, for example, by the following operation.

A mixture of the(R)-2-methyl-6-nitro-2-{4-[4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole,obtained in Example 19, (7.0 g), an activated carbon (0.7 g) and acetone(70 mL) were stirred under refluxing for 30 min. The activated carbonwas hot filtered, and washed with a small amount of acetone. Anactivated carbon (0.7 g) was added to the mother liquid, and the sameoperation was repeated. The mother liquid thus obtained was concentratedunder reduced pressure till the mother liquid became dried. The residuewas heat-dissolved in a mixed solution of ethanol (38.5 mL) and acetone(38.5 mL), then stirred at room temperature for 1 hour, and then cooledto 10° C. or less; and the precipitated crystal was filtered. Thecrystal was air blow-dried over night to obtain a target compound of5.746 g (82.09%).

Purity: 99.96% (HPLC)

HPLC conditions column: ODS-0TS (4.6φ×150 mm), detection wavelength: 254nm, mobile phase composition: 0.02M sodiumsulfate/tetrahydrofuran/acetonitrile=400/300/300, measurementtemperature: 40° C.

Optical purity: 99.97% ee (HPLC), HPLC conditions column: CHIRALPACKAD-H (4.6φ×250 mm), detection wavelength: 254 nm, mobile phasecomposition: n-hexane/ethanol/diethylamine=300/700/1

¹H-NMR (300 MHz, CDCl₃); 1.77 (3H, s), 1.8-2.2 (4H, m), 2.9-3.1 (2H, m),3.2-3.4 (2H, m), 3.9-4.1 (2H, m), 4.02 (1H, d, J=10 Hz), 4.04 (1H, d,J=10 Hz), 4.18 (1H, d, J=10 Hz), 4.4-4.5 (1H, m), 4.50 (1H, d, J=10 Hz),6.78 (2H, d, J=9 Hz), 6.8-7.0 (4H, m), 7.14 (2H, d, J=9 Hz), 7.56 (1H,s)

IR (KBr/cm⁻¹); 3133, 1609, 1513, 1340, 1038, 826

Powder X-ray (2θ): 5.26°, 7.88°, 10.52°, 15.76°, 21.06°

Jet mill-crushed product (average particle diameter: 2.2 μm)

Powder X-ray (2θ): 5.22°, 10.46°, 17.28°, 20.94°, 28.16°

Example 25 Synthesis of(R)-1-(4-oxiranylmethoxy)phenyl-4-(4-trifluoromethoxybenzyloxy)piperidine

31.26 kg of1-(4-hydroxyphenyl)-4-(4-trifluoromethoxybenzyloxy)piperidine4-methylbenzenesulfonic acid, 125 L of N,N-dimethylacetamide and 8.03 kgof potassium hydroxide were mixed, and stirred at room temperature. Themixture was mixed with 15.77 kg of (R)-oxiranylmethyl3-nitrobenzenesulfonate, stirred at 19 to 20° C. for 2.5 hours, andcooled to 10° C. or less. The mixture was mixed with 0.904 kg of sodiumdihydrogenphosphate dihydrate and 313 L of water, stirred at 50 to 60°C. for 0.5 hour; then, the crystal was filtered, washed with 156 L ofwater, and dried at 60° C. for 16 hours to obtain 24.06 kg of an ivorycrystal target substance.

Yield: 98.09%

HPLC purity: 94.7%

Optical purity: 99.5% ee (R-isomer)

¹H-NMR (300 MHz, CDCl₃)=1.70-1.90 (m, 2H), 1.98-2.12 (m, 2H), 2.70-2.77(m, 1H), 2.80-2.95 (m, 3H), 3.28-3.35 (m, 1H), 3.35-3.50 (m, 2H),3.50-3.65 (m, 1H), 3.88-3.94 (m, 1H), 4.12-4.18 (m, 1H), 4.56 (s, 2H),6.80-6.95 (m, 4H), 7.19 (d, 2H, 8.7 Hz), 7.38 (d, 2H, 8.8 Hz)

Example 26 Synthesis of(R)-1-(4-oxiranylmethoxy)phenyl-4-(4-trifluoromethoxybenzyloxy)piperidine

69.7 g of 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxybenzyloxy)piperidine4-methylbenzenesulfonic acid, 279 mL of N,N-dimethylacetamide, 17.9 g ofpotassium hydroxide (powder) and 31.0 g of (R)-oxiranylmethyl4-methylbenzenesulfonate were mixed. After stirring at 15 to 21° C. for21 hours, the mixture was mixed with 2.01 g of sodiumdihydrogenphosphate dihydrate and 697 mL of water. After stirring at 35to 45° C. for further 1 hour, the crystal was filtered, washed with 349mL of water, and dried at 50° C. for 48 hours to obtain 53.65 g of anivory crystal target substance.

Yield: 98.1%

HPLC purity: 97.9%

Optical purity: 84.6% ee (R-isomer)

Example 27 Synthesis of(R)-1-(4-oxiraneylmethoxy)phenyl-4-(4-trifluoromethoxybenzyloxy)piperidine

8.23 g of 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxybenzyloxy)piperidine4-methylbenzenesulfonic acid, 49.4 mL of N-methylpyrrolidone, 2.44 g ofsodium hydroxide, 24.7 mL of water, 8.28 g of tetrabutylammoniumhydrogensulfate and 2.82 g of (S)-epichlorohydrin were mixed. Afterstirring at 10° C. for 48 hours, the crystal was filtered, washed with148 mL of cooled water, dispersed in 49 mL of cooled water, andfiltered. The crystal was washed with 100 mL of cooled water, and driedat 50° C. for 18 hours to obtain 5.15 g of a target substance.

Yield: 79.8%

HPLC purity: 93.1%

Optical purity: 96.2% ee (R-isomer)

Example 28 Synthesis of a crude product of(R)-6-nitro-2-((4-(4-(4-trifluoromethoxy)benzyloxy)piperidin-1-ylphenoxy)methyl)-2,3-dihydroimidazo[2,1-b]oxazole

16.37 kg of(R)-1-(4-oxiranylmethoxy)phenyl-4-(4-trifluoromethoxybenzyloxy)piperidine,7.42 kg of 2-bromo-4-nitro-1H, imidazole, 16 L of N,N-dimethylacetamideand 630 g of sodium acetate were mixed, and stirred at 65 to 71° C. for8 hours; and the mixture was mixed with 131 L of N,N-dimethylacetamide.The mixture was cooled to −6° C., mixed with 3.25 kg of potassiumhydroxide, and stirred at −7 to −4° C. for 6 hours. The mixture wasmixed with 255 L of water and 13 L of ethyl acetate, and stirred, andthen allowed to stand over night. The mixture was stirred at 35 to 38°C. for 0.5 hour, and then cooled to 24° C.; the crystal was filtered,and washed with 82 L of water to obtain 32.44 kg of a wet crystal. 32.44kg of the wet crystal, 166 L of ethyl acetate and 158 L of methanol weremixed, and stirred and dissolved under heating and refluxing. Thesolution was stirred at 40 to 42° C. for 0.5 hour, and then stirred at10 to 4° C. for 1 hour; then, the crystal was filtered, washed with amixed liquid of 8 L of ethyl acetate and 8 L of methanol, and dried at60° C. for 7.5 hours to obtain 7,650 g of an ocherous crystal targetsubstance.

Yield: 37.02%

HPLC purity: 99.9%

Optical purity: 99.9% ee (R-isomer)

¹H-NMR (300 MHz, CDCl₃) δ=1.73-1.90 (m, 2H), 1.98-2.12 (m, 2H),2.80-2.95 (m, 2H), 3.30-3.50 (m, 2H), 3.50-3.65 (m, 1H), 4.20-4.35 (m,2H), 4.30-4.50 (m, 2H), 4.57 (s, 2H), 5.50-5.65 (m, 1H), 6.79 (d, 2H,9.2 Hz), 6.89 (d, 2H, 9.2 Hz), 7.19 (d, 2H, 9.4 Hz), 7.38 (d, 2H, 8.7Hz), 7.57 (s, 1H)

Example 29 Synthesis of a crude product of(R)-6-nitro-2-((4-(4-(4-trifluoromethoxy)benzyloxy)piperidin-1-ylphenoxy)methyl)-2,3-dihydroimidazo[2,1-b]oxazole

20.4 g of(R)-1-(4-oxiranylmethoxy)phenyl-4-(4-trifluoromethoxybenzyloxy)piperidine,7.13 g of 2-chloro-4-nitro-1H, imidazole, 20.4 mL of dimethoxyethane and3.08 g of potassium phosphate were mixed, stirred under refluxing for2.5 hours; then, the mixture was mixed with 163.2 mL ofN,N-dimethylacetoamide. The mixture was cooled to 0° C., mixed with 11.6g of a 25% sodium hydroxide aqueous solution, and stirred at 0° C. for2.5 hours. The mixture was mixed with 7.52 g of sodiumdihydrogenphosphate dihydrate and 367 mL of water, and stirred at 35 to40° C. for 1 hour; then, the crystal was filtered, mixed with 163 mL ofmethanol and 41 mL of water, and stirred at 50° C. for 0.5 hour; then,the crystal was filtered to obtain a wet crystal. The wet crystal, 153mL of ethyl acetate and 153 mL of methanol were mixed, and stirred anddissolved under heating and refluxing. The solution was stirred at 50°C. for 1 hour, and then stirred at 0° C. for 1 hour; then the crystalwas filtered, and dried at 60° C. over night to obtain 9.11 g of atarget substance.

Yield: 35.4%

HPLC purity: 95.9%

Optical purity: 99.9% ee (R-isomer)

Example 30 Purification to(R)-6-nitro-2-((4-(4-(4-trifluoromethoxy)benzyloxy)piperidin-1-ylphenoxy)methyl)-2,3-dihydroimidazo[2,1-b]oxazole

7.64 kg of the crude product of(R)-6-nitro-2-((4-(4-(4-trifluoromethoxy)benzyloxy)piperidin-1-ylphenoxy)methyl)-2,3-dihydroimidazo[2,1-b]oxazoleand 306 L of acetone were mixed, stirred at 15° C. for 10 min, mixedwith 380 g of an activated carbon, stirred at 15° C. for 15 min, andthen filtered. The filtrate was mixed with 380 g of an activated carbonand 8 L of acetone, and stirred at 15° C. for 15 min. The filteredfiltrate was concentrated under ordinary pressure to distill off 237 Lof acetone; then, 140 L of ethanol and 15 L of acetone were added to theresidue, and the residue was dissolved under refluxing; then, thesolution was stirred at 45 to 55° C. for 1 hour, stirred at 10° C. orless; then the crystal was separated, and dried at 60° C. for 18 hoursto obtain 6.329 kg of a light yellow crystal target substance.

Yield: 82.82%

HPLC purity: 100%

Optical purity: 99.97% ee (R-isomer)

The invention claimed is:
 1. An epoxy compound or a salt thereof,represented by the general formula (2):

wherein R¹ represents hydrogen or a lower alkyl group; R² represents apyperidyl group represented by the general formula (A1):

(wherein R³ represents: (A1a) a phenoxy group having ahalogen-substituted lower alkoxy group(s) as a substituent(s) on aphenyl group, (A1b) a phenoxy-substituted lower alkyl group having ahalogen-substituted lower alkyl group(s) as a substituent(s) on a phenylgroup, (A1c) a phenyl-substituted lower alkoxy lower alkyl group havinga halogen(s) as a substituent(s) on a phenyl group, (A1d) aphenyl-substituted lower alkyl group having a halogen-substituted loweralkoxy group(s) as a substituent(s) on a phenyl group, (A1e) an aminogroup having a phenyl group having a halogen-substituted lower alkoxygroup(s) as a substituent(s) on a phenyl group, and a lower alkyl group,or (A1f) a phenyl-substituted lower alkoxy group having ahalogen-substituted lower alkoxy group(s) as a substituent(s) on aphenyl group), or a pyperazyl group represented by the general formula(A2):

(wherein R⁴ represents: (A2a) a phenyl-substituted lower alkenyl grouphaving a halogen-substituted lower alkoxy group(s) as a substituent(s)on a phenyl group, or (A2b) a halogen-substituted phenyl group); and nrepresents an integer of 1 to
 6. 2. An epoxy compound or salts thereofselected from the group consisting of: 1)(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine;2)(R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine;3)(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethylphenoxymethyl)piperidine;4)(R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethylphenoxymethyl)piperidine;5)(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperazine;6)(R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperazine;7)(R)-4-(4-chlorobenzyloxymethyl)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]piperidine;8)(R)-4-(4-chlorobenzyloxymethyl)-1-[4-(2,3-epoxypropoxy)phenyl]piperidine;9)(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxybenzyl)piperidine;10)(R)-1-[4-(2,3-epoxypropoxy)phenyl]-4-(4-trifluoromethoxybenzyl)piperidine;11)(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[N-methyl-N-(4-trifluoromethoxyphenyl)]aminopiperidine;12)(R)-4-[N-methyl-N-(4-trifluoromethoxyphenyl)]amino-1-[4-(2,3-epoxypropoxy)phenyl]piperidine;13)(R)-1-(4-chlorophenyl)-4-[4-(2,3-epoxy-2-methylpropoxy)phenyl]piperazine;14) (R)-1-(4-chlorophenyl)-4-[4-(2,3-epoxypropoxy)phenyl]piperazine; 15)(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-(4-trifluoromethoxybenzyloxy)piperidine;and 16)(R)-1-(4-(oxiranylmethoxy)phenyl)-4-(4-(trifluoromethoxy)benzyloxy)piperidine.3. A method for manufacturing an epoxy compound or a salt thereofrepresented by the general formula (2):

wherein R¹, R² and n are the same as below, by reacting a compound or asalt thereof, represented by the general formula (3):

wherein R¹ represents hydrogen or a lower alkyl group; n represents aninteger of 1 to 6; and X² represents a halogen or a group causing asubstitution reaction similar to that of a halogen, with a compound or asalt thereof represented by the general formula (4):

wherein R² represents a pyperidyl group represented by the generalformula (A1):

(wherein R³ represents: (A1a) a phenoxy group having ahalogen-substituted lower alkoxy group(s) as a substituent(s) on aphenyl group, (A1b) a phenoxy-substituted lower alkyl group having ahalogen-substituted lower alkyl group(s) as a substituent(s) on a phenylgroup, (A1c) a phenyl-substituted lower alkoxy lower alkyl group havinga halogen(s) as a substituent(s) on a phenyl group, (A1d) aphenyl-substituted lower alkyl group having a halogen-substituted loweralkoxy group(s) as a substituent(s) on a phenyl group, (A1e) an aminogroup having a phenyl group having a halogen-substituted lower alkoxygroup(s) as a substituent(s) on a phenyl group, and a lower alkyl group,or (A1f) a phenyl-substituted lower alkoxy group having ahalogen-substituted lower alkoxy group(s) as a substituent(s) on aphenyl group), or a pyperazyl group represented by the general formula(A2):

(wherein R⁴ represents: (A2a) a phenyl-substituted lower alkenyl grouphaving a halogen-substituted lower alkoxy group(s) as a substituent(s)on a phenyl group, or (A2b) a halogen-substituted phenyl group).